The HbA1c blood test or glycosylated haemoglobin is used as a general indicator of average blood sugar levels present in plasma over about 3 months. There are many factors which can affect the results of an HbA1c test, such as any process affecting the red blood cell volume or turnover rate including blood loss, anaemia, surgery, blood transfusions, erythropoietin treatment as well as chronic kidney or liver disease and even high doses of vitamin C. Haemoglobin is the oxygen carrying component of a red blood cell and along with water, makes up the bulk of a red blood cell. An HbA1c test can be used to provide an average value for blood sugar levels over the preceding few weeks. TweetCustom Search The HbA1c blood test or glycosylated haemoglobin is used as a general indicator of average blood sugar levels present in plasma over about 3 months. Blood tests can reveal the overall health of your body, therefore, it is necessary to get a blood test at least once a year. Hyperglycemia is quite dangerous because you can die from it if it is not treated as early as possible.
By the time you are finished reading this paragraph, chances are a person somewhere will be dying of the disease. Sixth edition of the Diabetes Atlas by the International Diabetes Federation paints a grim picture. Most common complication of diabetes, cardiovascular disease manifests itself in form of angina, heart attack, congestive heart failure, stroke, and peripheral artery disease.
Neuropathy or damage to the nerves across the body can cause host of complications such as problems with urination and digestion, erectile dysfunction, and diabetic foot disease.
People with diabetes may injure a foot and not notice it due to neuropathy or loss of sensation. Gestational diabetes can cause fetal abnormalities, pregnancy complications or hypoglycemia in the newborn.
Sleep apnoea is the condition in which breathing stops for short intervals, up to 10 seconds, during sleep leading to buildup of carbon dioxide in the body. Siva Vallabhaneni is the Chief Operating Officer at DiaBliss, an organization committed to providing an alternate lifestyle to diabetics and pre-diabetics. He is holder of two worldwide patents, and has a B Tech in Chemical Engineering from Andhra University and M. Triglyceride, a fatty acyl ester derivative of glycerol, is the major energy depot of all eukaryotic cells. Lipogenesis is the process by which glycerol is esterified with free fatty acids to form triglyceride.
The cellular concentration of free fatty acids is tightly controlled by the balance between fatty acid esterification (described below) and triacylglycerol hydrolysis.
Adipose triglyceride lipase (ATGL) selectively performs the first and rate-limiting step, hydrolyzing triacylglycerols to generate diacylglycerols (DAGs) and free fatty acids. Hormone-sensitive lipase (HSL) is a multifunctional enzyme capable of hydrolyzing a variety of acylesters including triacylglycerol (TAG), diacylglycerol (DAG, and monoacylglycerol (MAG). The important role of adipose triglyceride lipase (ATGL) for triacylglycerol catabolism became evident from the analysis and examination of ATGL-deficient mice and human patients with mutations in the ATGL gene.
In contrast to ATGL deficiency, hormone-sensitive lipase (HSL)-deficient mice do not show increased fat deposition, are not overweight or obese, and lose white adipose tissue mass with increasing age. The tissue-specific expression pattern of hormone-sensitive lipase (HSL) resembles the one for adipose triglyceride lipase(ATGL).
Recently, a cell-cycle regulatory protein called G0G1 switch protein (GOS2) was identified as a selective inhibitor of adipose triglyceride lipase (ATGL)[1][2].
In non-adipose tissues, the activation of lipolysis is less well characterized because these tissues express little or no perilipin-1. Human adipose triglyceride lipase (ATGL) is phosphorylated at two serine residues (Ser404 and Ser428).
Adipose triglyceride lipase (ATGL) expression and activity is upregulated during adipose differentiation and is a target for transcription factors PPAR? and insulin-responsive transcription factor forkhead box O1 (FoxO1). Regulation of HSL - Adipose HSL activity is controlled by two distinct mechanisms in response to ?-adrenergic stimulation. Regulation of MGL - To date, no evidence exists that cellular monoglyceride lipse (MGL) mRNA concentrations or enzyme activities are regulated by either hormones or the energy state of the cell. Dietary fat (triglyceride) is hydrolyzed to free fatty acids and monoglycerol in the intestine by pancreatic lipase and the released free fatty acids and monoacylglycerols are absorbed by intestinal epithelial cells. An alternative source of triglycerides comes from their endogenous production in the liver.
In mammals, the synthesis of triacylglycerol serves critical functions in multiple physiological processes, including intestinal dietary fat absorption, intracellular storage of surplus energy, lactation, attenuation of lipotoxicity, lipid transportation, and signal transduction. MGATs - Monoacylglycerol acyltransferase (MGAT) catalyzes the first step in triacylglycerol synthesis involved in dietary absorption by enterocytes.
DGATs – As discussed above diacylglycerol, the obligate precursor to triglycerol, is derived either from the glycerol-3-phosphate pathway or the monoacylglycerol pathway and is esterified to triglycerol by a diacylglycerol acyltransferase (DGAT) reaction. Aberrant DGAT expression in any of several tissues or organ systems may play a role in disorders such as obesity and nonalcoholic fatty liver disease. Little is known about DGAT expression and regulation within the liver and the precise role of DGAT1 in the development of fatty liver syndromes such as nonalcoholic fatty liver disease remains to be determined.
The importance of triacylglycerol (TAG) synthesis is exemplified by severe insulin resistance in patients with lipodystrophy, a genetic condition characterized by defective TAG synthesis and storage in adipose tissues. The disease is advancing at an alarming rate, incapacitating the lives of 382 million people.
On a cellular level, insulin acts as a gatekeeper allowing the cells to take in glucose and expend it as energy.
People with type I diabetes, nearly 20% of diabetic population, can’t produce insulin and thus are dependent on insulin therapy. Left unchecked, high blood glucose levels can irreparably damage heart and blood vessels, kidneys, eyes, and nerves. The pitchfork of high blood pressure, high cholesterol, and high blood glucose is the culprit behind the onset of cardiovascular disease in diabetics. Again, the triumvirate of high blood glucose, high blood pressure and cholesterol are to blame. Moreover, the child born to a diabetic mother has a high risk of developing type II diabetes later in life. Lipolysis is the enzymic process by which triacylglycerol, stored in cellular lipid droplets, is hydrolytically cleaved to generate glycerol and free fatty acids. Compared to its hydrolytic activity towards triacylglycerol (TAG), ATGL exhibits only minor or no activity against other lipids, such as diacylglycerol (DAG), monoacylglycerol (MAG), cholesterylesters, or retinylesters[1]. Within the triacylglycerol hydrolysis cascade this enzyme is rate-limiting for DAG catabolism. ATGL mutations in humans are associated with systemic triacylglycerol accumulation and cardiac myopathy with this rare inherited disease referred as “neutral lipid storage disease with myopathy”[1].
It is predominantly expressed in adipose tissue and liver and to a lesser extent in muscle, ovary, and kidney. However, the relevance of phosphorylation for the regulation of enzyme activity is unclear. Furthermore, fasting and glucocorticoids such as dexamethasone, the PPAR? agonists thiazolidinediones, induce mRNA expression.
Firstly, the enzyme is phosphorylated by cAMP-dependent PKA at at least five distinct serine residues. Short chain fatty acids can enter the circulation directly, but most fatty acids are re-esterified to triacylglycerols in the mucosa (the lining) of the intestine and packaged with other lipids and apoprotein B-48 to form small fat globules called chylomicrons. Lipogenesis is the process by which end products of glucose catabolism are converted to fatty acids, which are subsequently esterified with glycerol to form the triacylglycerols that are packaged in very-low-density lipoproteins (VLDLs) and secreted from the liver[5]. Three isoforms of MGAT enzymes, known as MGAT1, MGAT2, and MGAT3, have been identified so far. There are at least two independent mammalian enzymes known to catalyze this reaction, DGAT1 and DGAT2, both of which show little preference in terms of the fatty acyl-CoA substrate[8].


Glucose preferentially enhances DGAT1 mRNA expression, whereas insulin increases the level of DGAT2 mRNA. DGAT1 was unable to compensate for the loss of DGAT2, suggesting different roles for the two enzymes, and that DGAT2 is the enzyme responsible for the majority of triglyceride synthesis in mice[8]. DGAT1 expression was found to be upregulated in the livers of individuals with this syndrome[8]. Monoacylglycerol acyltransferase (MGAT) and diacylglycerol acyltransferase (DGAT) enzymes are implicated in multiple pathways that regulate energy homeostasis.
Whereas excess TAG accumulation in adipose leads to obesity, ectopic storage of TAG in nonadipose tissues such as liver and skeletal muscle is associated with insulin resistance. In lack of insulin, the glucose keeps circulating in the blood causing damage to body tissues as it travels without being used. In type II diabetes, body produces insulin but cells fail to use it effectively, sometimes leading to absolute insulin deficiency. These complications notwithstanding, diabetes makes healing of wounds close to impossible and risk of infections always looms large. Kidneys have a network of tiny blood vessels which are at risk when blood in them is high in glucose levels. Loss of feeling is particularly dangerous as it may lead to injuries to go undetected, and thereby raising the risk of infections and ulcers which ultimately result in amputation.
Besides, there are many changes in the skin quality such as peeling or cracking, that expose the foot to infection. Diabetic mothers must monitor and manage their condition and seek medical advice from the beginning of their pregnancy. The free fatty acids can be subsequently used as energy substrates, essential precursors for lipid and membrane synthesis, or mediators in cell signaling processes. Being apolar (poorly water-soluble), triglycerides are transported in the form of plasma-lipoproteins called chylomicrons.
Triacylglycerol storage and mobilization is a general biological process in essentially all cells of the body and is not restricted to adipose tissue. Finally, monoglyceride lipase (MGL) efficiently cleaves MAG into glycerol and non-esterified fatty acids (free fatty acids)[1].
Notably, these mice accumulate diacylglycerol (DAG) in several tissues indicating that HSL is rate-limiting for DAG hydrolysis. Low HSL expression is found in many other tissues and cells particularly in steroidogenic cells, muscle, pancreatic ?-cells, and macrophages[1]. Epinephrine and glucagon stimulate fatty acid release from triglycerides stored in adipocyte fat droplets, whereas insulin action is to counter the responses to these two hormones, and conversely, to induce fat storage.
In the absence of ATGL, free fatty acid and glycerol mobilization in response to ?-adrenergic stimulation were decreased by ?70%. Thus, alternative, perilipin-1-independent mechanisms must exist to regulate ATGL activity in non-adipose tissues and could involve perilipin-2, the ubiquitously expressed protein that regulates the access of ATGL to lipid droplets in various cell lines. In contrast to hormone-sensitive lipase (HSL) (see below), phosphorylation of ATGL does not involve PKA. Besides PKA, other protein kinases have also been shown to phosphorylate HSL and regulate enzyme activity. High MAG hydrolase activity levels are constitutively present in adipocytes, hepatocytes, and muscle cells suggesting that this activity is not subject to extensive regulation.
The major function of glycolysis in the liver is to provide carbons from glucose for de novo lipid synthesis[6]. The monoacylglycerol pathway begins with the acylation of monoacylglycerol with a fatty acyl-CoA by monoacylglycerol acyltransferase. The monoacylglycerol (MAG) pathway, begins with the acylation of MAG with fatty acyl-CoA catalyzed by monoacylglycerol acyltransferase (MGAT). All three possess strong monoacylglycerol acyltransferase enzyme activity and are localized in the endoplasmic reticulum (ER).
In humans, DGAT1 is highly expressed in human small intestine, colon, testis, and skeletal muscle but has notably lower levels of expression in adipose and liver. Interestingly when fasted mice are fed a high-carbohydrate meal, DGAT2 but not DGAT1 mRNA is increased in liver, adipose, and small intestine[8]. MGAT and DGAT enzymes play important roles in energy metabolism by regulating satiety in the brain (mediated by monoacylglycerol (MAG)), dietary fat absorption in the gut (in the form of triacylglycerol (TAG)), phospholipid synthesis and very-low-density lipoprotein (VLDL) secretion in the liver (in the form of DAG and TAG), fat storage in adipocytes (in the form of TAG), and insulin sensitivity in skeletal muscle (mediated by DAG).
Recent progress in the identification and characterization of the monoacylglycerol acyltransferase (MGAT) and diacylglycerol acyltransferase (DGAT) enzymes along with the phenotypic characterizations of mice with altered expression of these genes have provided important insights into their dynamic roles in the regulation of energy homeostasis and other physiological functions[7]. Another 175 million people remain undiagnosed and unaware of the potential complications of diabetes.
Regular exercise and consuming low Glycemic Index (GI) foods can go a long way in improving health of diabetics, and pre-diabetics. The complete oxidation of free fatty acids to generate ATP occurs in the mitochondria by the processes of ?-oxidation which is described in the related article Fatty acid oxidation and synthesis.
Lipids are released from their carrier lipoproteins through the local activity of lipoprotein lipase (LPL) and subsequently split into their constituent fatty acids and glycerol.
However, whereas adipocytes are able to secrete free fatty acids and provide them as systemic energy substrates, non-adipose cells do not secrete fatty acids but utilize triacylglycerol-derived fatty acids in a cell autonomous manner for local energy production or lipid synthesis. Mutations in the HSL gene of humans leading to enzyme dysfunction or deficiency have not been reported.
Epinephrine and glucagon, binding to their respective receptors, triggers activation of adenylate cylcase (AC) and subsequently, PKA. In adipocytes, its expression is induced by insulin and inhibited by TNF-? or isoproterenol, both factors that stimulate lipolysis.
The molecular mechanisms that regulate ATGL activity in response to ?-adrenergic stimulation are incompletely understood. Whether the regulation of ATGL activity by perilipin-2 in adipose and non-adipose tissues involves the reversible binding of ABHD5 by perilipin-2 is currently unknown. Furthermore, the known phosphorylation sites are not critical for lipid droplet localization or in vitro triacylglycerol (TAG) hydrolysis. Interestingly, the ?-adrenergic agonist isoproterenol reduces ATGL (and HSL) mRNA levels in adipocytes although the enzyme activity is induced at the same time. The word chylomicron is composed of "chylo" - milky and "micron" - small; ie small milky (globules)[4]. This pathway plays a predominant role in enterocytes (columnar epithelial absorptive cells of the small intestine) after feeding, where large amounts of 2- monoacylglycerol and fatty acids are released from the digestion of dietary lipids. This pathway dominates in the small intestine, a tissue primarily responsible for dietary fat absorption.
In contrast DGAT2 while showing widespread expression in humans, is found in particularly high levels in liver and adipose tissue. Gestational diabetes affects pregnant women and poses significant health risks to the mother and child.
It becomes imperative to keep glucose levels in check by switching to low GI diet to avoid nephropathy. It involves the sequential degradation of fatty acids to multiple units of acetyl-CoA which can then be completely oxidized via the tricarboxylic acid cycle (Krebs Cycle) and electron transport chain. These are taken up by adipose tissue where the triglycerides are resynthesized and stored in cytoplasmic lipid droplets. Consistent with this local utilization, the triacylglycerol storage capacity of non-adipose tissues and cells is relatively minor compared to the importance of adipose tissue providing fatty acids for the whole organism. The physiological role of monoglyceride lipse (MGL) in lipolysis has not been evaluated so far[1].
Furthermore G0S2 has been identified as a peroxisome proliferator-activated receptor gamma (PPAR?) target gene containing a PPAR-response element (PPRE) in its promoter sequence.
Secondly, phosphorylated HSL interacts with the lipid droplet protein perilipin-1, which itself is a target of PKA phosphorylation.
The monoacylglycerol pathway is also active in adipose tissue, likely playing a role in storing excess energy in the form of triacylglycerol[7].


The glycerol 3-phosphate (G-3-P) pathway is a de novo pathway involved in triacylglycerol (TAG) synthesis in most tissues. The MGAT1 mRNA has been detected mainly in stomach, kidney, and adipose tissue, whereas MGAT2 and MGAT3 exhibit highest expression in the small intestine. These expression patterns of the DGATs indicate that they may have different functions in different tissues.
Lipogenesis also includes the anabolic process by which triglycerides are formed in the liver from excess glucose.
In fact, excessive ectopic lipid deposition in non-adipose tissues leads to lipotoxicity and is associated with prevalent metabolic diseases, such as type-2 diabetes[1]. To date, three enzymes: adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL) and monoglyceride lipase (MGL) have been implicated in the complete hydrolysis of triacylglycerol molecules in cellular lipid stores (Figure 1). Perilipin-1 expression is restricted to ?-adrenergic stimulatable cells, such as adipocytes and steroidogenic cells, and is essential for ?-adrenergic stimulatable lipolysis.
In murine hepatocytes, downregulation of perilipin-3 expression leads to a dramatic increase of lipid droplet size and a decrease in lipid droplet number.
Leptin is known to restrain energy intake and to promote lipolysis, a process involving upregulation of PPAR? expression. The translocation of phosphorylated HSL to the lipid droplet in white adipose tissue is mediated by the phosphorylated form of perilipin-1.
Chylomicrons bind to membrane-bound lipoprotein lipases, primarily at adipose tissue and muscle, where the triacylglycerols are once again hydrolysed into free fatty acids and monoacylglycerol for transport into the tissue. The G-3-P pathway begins with the acylation (with fatty acyl-CoA), of G-3-P by glycerol-3-phosphate acyltransferase (GPAT), producing lysophosphatidic acid (LPA). Among the MGAT isoforms, MGAT3 (which is found only in higher mammals and humans but not in rodents) possesses some unique features. DGAT1 likely plays a role in intestinal repackaging of free fatty acids using the monoacylglycerol pathway, whereas DGAT2 may function primarily in triglyceride synthesis and export from the liver and deposition in adipose tissue [8]. DAG is an activator for protein kinase C (PKC), which regulates insulin sensitivity in the liver and skeletal muscle.
Here fatty acids of varying length are synthesised by the sequential addition of two-carbon units derived from acetyl CoA as discussed in the related article Fatty acid oxidation and synthesis. The N-terminal domain of G0S2 directly interacts with the patatin domain of ATGL facilitating AGTL’s binding to lipid droplets[2]. Perilipin-1 governs the ATGL- and HSL-mediated breakdown of fat in white adipose tissue in multiple ways (see below).
In addition, these cells show increased lipolysis associated with increased ATGL localization on lipid droplets.
Yet, a study on porcine adipocyte lipolysis found that leptin decreased ATGL protein expression while it increased mRNA expression. In the basal, non-hormonally stimulated state, perilipin-1 is not phosphorylated and prevents the binding of HSL to lipid droplets. The triacylglycerols are then resynthesized inside the cell and stored as fat in adipose tissue or used for energy by the process called ?-oxidation in any tissue with mitochondria and an ample supply of oxygen.
This is followed sequentially by further acylation by LPA acyltransferase (LPAAT) and dephosphorylation by phosphatidic acid (PA) phosphorylase (PAP) to yield diacylgycerol (DAG). Although named after its enzyme activity, MGAT3 shares higher sequence homology and some catalytic properties with DGAT2 than with the other MGAT isoforms, suggesting MGAT3 also functions as a triacylglycerol synthase[7].
2-Arachidonoylglycerol in the brain is a natural ligand for endocannabinoid receptors, which regulate various physiological events, including appetite.
Fatty acids generated by lipogenesis in the liver, are subsequently esterified with glycerol to form triglycerides that are packaged, not in chylomicrons, but in very low density lipoproteins (VLDLs) and secreted into the circulation. Free fatty acids are transported to the plasma membrane bound to adipocyte fatty acid-binding protein (aP2: also known as FABP4) and transported across the plasma membrane into the circulation by one of several fatty acid transport proteins. As discussed above ATGL activity is regulated by the availability of its co-activator ABHD5.
Thus, perilipin-3 exerts a protective role for lipid droplet via preventing ATGL access to the lipid droplet. Insulin resistance and obesity have also been correlated with changes in ATGL mRNA or protein levels[1].
In response to ?-adrenergic stimulation, perilipin-1 is phosphorylated on six consensus serine residues by PKA. The 2 pathways share the final step in converting diacylglycerol DAG into TAG, which is catalyzed by diacylglycerol acyltransferase (DGAT). Consequently, the MGAT and DGAT families of enzymes are implicated in the regulation of various physiological functions, such as dietary fat absorption, lipid metabolism, fat storage, insulin sensitivity, satiety, and energy homeostasis (Figure 4). Once in the circulation, VLDLs come in contact with lipoprotein lipase (LPL) in the capillary beds in the body (adipose, cardiac, and skeletal muscle) where LPL releases the triglycerides for intracellular storage or energy production.
The glycerol released through the action of monoglyceride lipase (MGL) is transported across the plasma membrane via the action of aquaporin 7, (AQP7). In non-stimulated adipocytes, ABHD5 is located at the surface of lipid droplets and is mostly bound to perilipin-1. Perilipin-4 is found primarily in white adipose tissue and to a lesser degree in skeletal muscle and heart but nothing is known about its involvement in the lipolytic pathway. Whether matching regulatory phosphorylation sites exist on mammalian ATGL orthologues and whether they are involved in enzyme inactivation during hibernation, long-term fasting, etc. Specifically the phosphorylation of serines 81, 222, and 276 induce the binding of HSL to perilipin-1 and access to the lipid droplet. DAG is also used as a substrate for the synthesis of phosphatidic choline (PC) and phosphatidic ethanolamine (PE). The actions of insulin, which counter the effects of epinephrine or glucagon, are primarily the result of the activation of PKB which then phosphorylates and activates phosphodiesterase (PDE) leading to a reduced level of cAMP and consequent reduced activity of PKA.
In the activated state, perilipin-1 is phosphorylated by cAMP-dependent protein kinase A (PKA) which causes the dissociation of ABHD5 from perilipin-1, which is now available for the activation of ATGL (Figure 2).
A fifth member of the family, perilipin-5 was identified as a lipid droplet binding protein that may regulate fatty acid mobilization and oxidation in tissues with high oxidative capacity such as liver and muscle[1]. After full hormonal stimulation, HSL phosphorylation and the perilipin-1-mediated translocation of the enzyme to the lipid droplet causes a ?100-fold induction of HSL activity in white adipose tissue. Thus perilipin-1 controls the activation of ATGL in white adipose tissue by interacting with its co-activator ABHD5 in a cAMP-dependent fashion[1][2].
In non-adipose cells lacking perilipin-1, the role of HSL is less well characterized[1][2].
This pathway begins with the acylation of glycerol 3-phosphate with a fatty acyl-CoA, producing lysophosphatidic acid, followed by further acylation and dephosphorylation to yield diacylglycerol. These two pathways share the final step in converting diacylglycerol to triacylglycerol, a reaction catalyzed by diacylglycerol acyltransferase[7]. It was originally named comparative gene identification-58 (CGI-58) following a comparative gene sequence screen of humans and the nematode C.
This activation involves direct protein-protein interaction with ABHD5 with maximal stimulation achieved at approximately equimolar concentrations of enzyme and activator protein.
Currently, it is unknown whether ABHD5 binding affects ATGL conformation, facilitates substrate presentation, or enhances ATGL’s lipolytic activity by removing reaction products from the active site. The direct interaction by itself is not sufficient since ABHD5 variants, which were capable of binding ATGL, failed to stimulate enzyme activity. ATGL activation in living cells additionally requires the binding of ABHD5 to the lipid droplet.
Truncated variants of ABHD5, which fail to localize to the lipid droplet, but bind to ATGL, are unable to stimulate ATGL activity[1][2].



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